Process for preparing farnesyl acetic acid esters and 2-substituted-products thereof

ABSTRACT

Process for preparing farnesyl acetic acid esters represented by the general formula:   WHEREIN R1 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group or an aryl group and R5 is the same as R2, R3 or R4 hereinafter defined, which process comprises reacting nerolidol (3, 7, 11-trimethyl-1, 6, 10-dodecatrien-3-ol) represented by the formula:   WITH 2-SUBSTITUTED ORTHOACETIC ACID ESTER DERIVATIVES REPRESENTED BY THE GENERAL FORMULA:   wherein R2, R3 and R4, which are the same or different, each represents an alkyl group or a cycloalkyl group, in the presence of an acidic catalyst.

United States Patent 91 Fujita et a].

Dec. 23, 1975 PROCESS FOR PREPARING FARNESYL ACETIC ACID ESTERS AND Z-SUBSTITUTED-PRODUCTS THEREOF [75] Inventors: Yoshiii Fujita, Kurashiki; Yoshiaki Omura, Okayama; Takashi Nishida; Kazuo Itoi, both of Kurashiki, all of Japan [73] Assignee: Kuraray Co., Ltd., Kurashiki, Japan [22] Filed: July 10, 1974 [56] References Cited UNITED STATES PATENTS 3,154,570 10/1964 Adami ..260/410.9R

OTHER PUBLICATIONS Chemical Abstracts, 50:8445d. Helv. Chim. Acta. 53, pp. 1827-1832, (1970).

Primary Examiner-Winston A. Douglas Assistant ExaminerJohn F. Niebling Attorney, Agent, or Firm-Bacon & Thomas ABSTRACT Process for preparing famesyl acetic acid esters represented by the general formula:

wherein R, represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group or an aryl group and R is the same as R R or R hereinafter defined, which process comprises reacting nerolidol (3, 7, lltrimethyl-i, 6, l0-dodecatrien-3-ol) represented by the formula:

WW (I) with Z-substituted orthoacetic acid ester derivatives represented by the general formula:

wherein R R and R,,, which are the same or different, each represents an alkyl "group or a cycloalkyl group, in the presence of an acidic catalyst.

12 Claims, No'fii'awings PROCESS FOR PREPARING FARNE SYL ACETIC ACID ESTERS AND Z-SUBSTITUTED-PRODUCTS THEREOF BACKGROUND OF THE INVENTION 1. Field of the Invention ing 2-substituted or unsubstituted farnesylacetic acid esters which are useful as antiulcer agents (see, e.g., US. Pat. No. 3,154,570).

2. Description of the Prior Art Z-Unsubstituted farnesylacetic acid esters have heretofore been prepared by reacting nerolidol represented by the formula: I

I OH with phosphoorus tribromide to give farnesyl bromide represented by the formula:

wherein R,, represents an alkyl group, and then subject ing (V) to hydrolysis, decarboxylation and esterification (Helv. Chim. Acta, 53, 1827 I832 (1970)).

SUMMARY OF THE INVENTION Farnesylacetic acid esters of the above formula (III) may be effectively prepared in a single step in good yield by the process of the present invention which comprises reacting nerolidol (I) with a 2-substituted orthoacetic acid ester derivative represented by the general formula:

wherein R, represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, or an aryl group; and R R and R,, which are the same or different, each represents an alkyl group or a cycloalkyl group, in the presence of an acidic catalyst. Among of the products produced by the present invention, 2-substituted farnesylacetic acid esters represented by the general formula:

COOR W I s 2 wherein R, represents hydrocarbon radical of l to 20 carbon atoms, such as, an alkyl group of l to 20 carbon atoms, a cycloalkyl groupof 6 to 20 carbon atoms, an alkenylgro'up of:2 to 20 carbon atoms, a cycloalkenyl groupof 6 to 20 carbon atoms an alkynyl group of 2 to 20 carbon atoms or an aryl group of 6 to 20 carbon atoms and wherein R represents one of R R or R, as defined in formula (II) are novel and useful compounds The present invention relates toaprocess for preparespecially as anti-ulcer agents as well as 2-unsubstituted farnesylacetic acid described in US. Pat. No. 3,154,570. The compounds 2-cyclohexyl farnesyl acetate and 2-phenyl farnesyl acetate described hereinafter in Examples 8 and 9 have been found to be particularly good anti-ulcer agents and can also be advantageously employed in the treatment of dermatosis.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The Z-substituted or unsubstituted farnesylacetic acid esters produced by the process of the present invention are represented by the general formula:

COOR

wherein R, is as defined in formula (II) and wherein R,-, represents one of R R or R, as defined in formula (II).

More specifically, R, may be a hydrogen atom, an ally] group of l to20 carbon atoms (e.g.,.methyl ethyl, propyl, butyl, amyl, decyl, pentadecyl, eicosyl, etc.),- a cycloalkyl group of 6 to 20 carbon atoms (e.g.,: cyclohexyl, cycloheptyl,cyclodecyl, etc.), an alkenyl group of 2 to 20 carbon atoms (e.g., vinyl, allyl, penten'yl, octenyl, decenyl, nonadecenyl etc.). a cycloalkenyl group of 6 to 20- carbon atoms (e.g., l-cyclohexenyl. etc.), an alkynyl group of 2 to 20 carbon atoms (e.g., ethynel, propynyl, hexynyl. decynyl, etc.), or an aryl group of 6 to 20 carbon atoms (e.g., phenyl, naphthyl,

etc.)

R R and R, may be the same 'or different and each represents an alkyl group of. l to 8 carbon atoms"(e.g.', methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, etc.), or a cycloalkyl group of 3 to 8 carbon atoms (e.g., cyclopropyl cyclohexyl, cyclooctyl, etc.). i

R,, R R and R, each may have a total number of carbon atoms outside of the above ranges. Broadly, R, may be a hydrogen atom or any hydrocarbon radical .having from I to-20 carbon'atoms, including those lower fatty acids (e.g., acetic acid, propionic acid. bu-

tyric acid, isobutyric acid, valeric acid, malonic acid, succinic acid, adipic acid, etc); sulfonic acids'(e.g., p-toluene-sulfonic acid, etc.); mineral acids (e.g., hy-

drochloric acid, sulfuric acid, etc); and Lewis acids (e.g., zinc chloride, ferrouschloride'boron trifluoride, aluminum chloride, etc.). Asuitable amount of the catalyst is 0.1 to percent by weight, pr'eferably '1 to 10 percent by weight, based on the weight of the-neroli- ClOl. i i a A solvent is not necessary in 'the reaction but inert These reactions are effected as in Example 1 except that various orthoorganic esters are used, as shown in the following table along with the results.

, TABLE Example Amount of ()rthocstcr Acidic Reaction Product Boiling Yield Ncrolidol Catalyst Conditions Point (/1 (C., hours) (C/mm Hg) 2 44.8g CH;;C(OEt);,, isobutyric l135 ethyl farncsyl- 163-167C 93.2

acid 2.3g 21 hr. acctate (2mm Hg) 3 CH.-IC(OP 1 isobutyric 133-l38 propyl farncsyll47l5()C 914 I acid 2.3g 28 hr. I acetate (0.5 mm Hg) 4 M" (H;,((Onl-3u); n-hutyric l'35l42 n-butyl farnesyl- 145-148C 90.0

v acid 4.0g 43 hr. acetate (0.5mm Hg) 5 C (0 adipic MCI-145 cyclohcxyl farncsyl l62-164C 90.7

' acid 1.2g 48 hr. acetate (0.3mm Hg) 6 CH; CH:C(()Mc propionic 125-1 27 methyl-Z-mcthyl Bil-140C 94.2

, 1 acid 0.9g 19 hr. farncsylacctate (p.2mm Hg) 7 CH;,CH ,CH C(OEt) oxalic 129-132 ethyl-Z-cthyl 144-146C 93.8

' acid 0.2g 43 hr. l'arnesylacetate (p.2mm Hg) x 1 1.2g @-c H -c (05:) isohutyric 130-135 ethyl-Z-cyclohexyl 170-1 75C 91.6

3 acid 1.1g 8 hr. farnesylacctatc (0.2mm Hg) 9 1 1.2g -c n -uom) adipic 140445" ethyl-Z-phenyl separated by 247.2

3 acid 0.6g 19 hr. i'arnesylacetate column chromatography on silica gel solvents such as n-heptane, n-octane, benzene, toluene,

EXAMPLE l0 o-xylene, m-xylene and p-xylene may be. used. Alternatively, the Z-substituted orthoacetic acid esters may be used in excess in the form of a solvent;

The reaction may be effected at 50 to 200C, preferably 100 to 150C. in view of the reaction rate and selectivity, although the temperature is not-critical and may vary outside of these ranges.

The nerolidol andv Z-substituted orthoacetic acid esterderivative (11) should preferably be employed in.

about equimolar amounts, although the molar ratio of 40 theformer to the latter may be anywhere" within the range of from 1/l.l to 1/4.

The time of reaction is not critical and may vary from 2 to 30-hours. It is preferred that the alcohol which is formed as a by-product-be removed during the reaction by distillation. The product farnesyl acetic acid ester may be. recovered by first removing low boiling components from the reaction mixture (such as the catalyst and any unreacted. Z-substituted orthoacetic acid ester derivative) and distilling the residue.

The following examples are intended to illustrate the invention as applied to representative products and are further for the purpose of illustrating the best mode contemplated for carrying out the invention and to supplement the foregoing disclosure of the invention with additional descriptions of the manner and process of carrying out the invention so as further to enable those skilled in the art to do so.

EXAMPLE 1 ture is then evaporated, as is, to remove the low-boiling materials such as butyric acid, whereby the unreacted 1,1,l-trimethoxyethane is recovered. The residue is distilled under high vacuum to give the objective Into a mixture of acrylonitrile (41g) and cyclohexanol g) cooled at 0 to 2C., dry hydrogen chloride gas is introduced under stirring to precipitate the corresponding iminoether hydrochloride. Methanol (64g) is added at not more than 10C. thereto, and the reaction is effected at 20 to 25C. for 6 hours, whereby 1.1- dimethoxy-l-cyclohexyl-oxyethane is obtained in a yield of 62 percent.

A mixture of nerolidol 1 1.2g), 1,1-dimethoxy-lcyclohexyloxyethane (20g) and butyric acid (0.6g) is heated at to C. for 32 hours. The reaction products are assayed by gas chromatography, wherein the conversion of nerolidol is almost 100 percent. The methyl ester obtained in Example 1 and the cyclohexyl ester obtained in Example 5 are prepared in a ratio of 3:7 by weight.

While the invention has been shown and described by reference to preferred embodiments thereof, it is to be expressly understood that various changes, modifications and/or substitutions may be made therein without departing from the spirit and scope thereof, it being the intention that the invention be limited only by the scope of the appended claims.

What is claimed is:

l. A process for preparing farnesyl acetic acid esters of the formula (1):

CH3 x bon radical of 1 to 20 carbon atoms. and R,-, is the same as R R or R, below in formula (11). said process comprising reacting nerolidol with a Z-substituted orthoacetic acid ester derivative of the formula (ll):

wherein R, is as defined in formula (I) above and R R and R which may be the same or different, each represents an alkyl group of l to 8 carbon atoms or a cycloalkyl group of 3 to 8 carbon atoms; in the presence of an acidic catalyst.

2. The process of claim 1, wherein said R is a hydrogen atom, an alkyl group of l to carbon atoms, a cycloalkyl group of 6 to 20 carbon atoms, an alkenyl group of 2 to 20 carbon atoms, an alkynyl group of 2 to 20 carbon atoms, a cycloalkenyl group of 6 to 20 carbon atoms or an aryl group of 6 to 20 carbon atoms.

3. The process of claim 1, wherein the temperature of reaction is from 50 to 200C.

4. The process of claim 1, wherein the reaction is performed in an inert solvent.

5. The process of claim 1, wherein the catalyst is employed in an amount of from 0.1 to 20 percent by weight, based on the weight of the nerolidol.

6. The process of claim 5, wherein said acidic catalyst is a weak acid.

7. The process of claim 6, wherein said acid is a lower fatty acid, a sulfonic acid, a mineral acid or a Lewis acid.

8. The process of claim 1, wherein said nerolidol and said 2-substituted orthoacetic acid ester are employed in substantially equimolar amounts.

9. The process of claim 1, wherein the molar ratio of said nerolido] to said Z-substituted orthoacetic acid ester is from l/l.l to 1/4.

10. The process of claim 1, wherein said 2-substituted orthoacetic acid ester is selected from the group consisting of l,l,l-trimethoxyethane, l,l.l-triethoxyethane, l,1,l,-tripropoxyethane, 1, l l tricyclohexyloxyethane, 1,1,l-tri (n-butoxy) ethane, l,l.ltrimethoxypropane, 1,1 l -triethoxypropane, 1, 1 -dimethoxyl -cyclohexyloxyethane, l ,1 ,l-triethoxybutane, 1,1, l-triethoxy-2-cyclohexylethane, and 1, l l-triethoxy-2-phenylethane.

11. A Z-substituted farnesyl acetic acid ester represented by the general formula:

wherein R, is an alkenyl group of 2 to 20 carbon atoms. a cycloalkenyl group of 6 to 20 carbon atoms, an alkynyl group of 2 to 20 carbon atoms or an aryl group of 6 to 20 carbon atoms, and wherein R,-, is an alkyl group of l to 8 carbon atoms or a cycloalkyl group of 3 to 8 carbon atoms.

12. An ester of claim 11 wherein said R is phenyl radical.

Patent No.

Inventor(s) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 3 ,928,403 Dated December 23, 1975 Yoshiji Fuj ita, Yoshiaki Omura, Takashi Nishida and Kazuo Itoi It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the following designated places "2-substituted" should ABSTRACT,

Column 1,

Column 3,

Column Column Column [SEAL] read unsubstituted and 2-substituted first line after formula I, after "with";

line 47, after "with";

line 32, after "the";

line 38, after "and";

line 49, after "unreacted";

line 2, after "said";

line 5, after "said";

line 7, after "said".

lines 11 and 12 should read esters which are useful as antiulcer agents or intermediates to produce the same (see, e.g. U.S. Patent No.

lines 1 and 2 should read prising reacting nerolidol with an unsubstituted and 2- substituted orthoa- Arrest:

RUTH C. MASON A nesting Officer C. MARSHALL DANN (nmmissiuner ufPatents and Trademarks 

1. A PROCESS FOR PREPARING FARNESYL ACETIC ACID ESTERS OF THE FORMULA (I):
 2. The process of claim 1, wherein said R1 is a hydrogen atom, an alkyl group of 1 to 20 carbon atoms, a cycloalkyl group of 6 to 20 carbon atoms, an alkenyl group of 2 to 20 carbon atoms, an alkynyl group of 2 to 20 carbon atoms, a cycloalkenyl group of 6 to 20 carbon atoms or an aryl group of 6 to 20 carbon atoms.
 3. The process of claim 1, wherein the temperature of reaction is from 50* to 200*C.
 4. The process of claim 1, wherein the reaction is performed in an inert solvent.
 5. The process of claim 1, wherein the catalyst is employed in an amount of from 0.1 to 20 percent by weight, based on the weight of the nerolidol.
 6. The process of claim 5, wherein said acidic catalyst is a weak acid.
 7. The process of claim 6, wherein said acid is a lower fatty acid, a sulfonic acid, a mineral acid or a Lewis acid.
 8. The process of claim 1, wherein said nerolidol and said 2-substituted orthoacetic acid ester are employed in substantially equimolar amounts.
 9. The process of claim 1, wherein the molar ratio of said nerolidol to said 2-substituted orthoacetic acid ester is from 1/1.1 to 1/4.
 10. The process of claim 1, wherein said 2-substituted orthoacetic acid ester is selected from the group consisting of 1,1,1-trimethoxyethane, 1,1,1-triethoxyethane, 1,1,1,-tripropoxyethane, 1,1,1-tricyclohexyloxyethane, 1,1,1-tri (n-butoxy) ethane, 1,1,1-trimethoxypropane, 1,1,1-triethoxypropane, 1,1-dimethoxy-1-cyclohexyloxyethane, 1,1,1-triethoxybutane, 1,1, 1-triethoxy-2-cyclohexylethane, and 1,1,1-triethoxy-2-phenylethane.
 11. A 2-substituted farnesyl acetic acid ester represented by the general formula:
 12. An ester of claim 11 wherein said R1 is phenyl radical. 